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Stressed erythrophagocytosis induces immunosuppression during sepsis through heme-mediated STAT1 dysregulation
Tolani F. Olonisakin, … , Prabir Ray, Janet S. Lee
Tolani F. Olonisakin, … , Prabir Ray, Janet S. Lee
Published September 17, 2020
Citation Information: J Clin Invest. 2021;131(1):e137468. https://doi.org/10.1172/JCI137468.
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Research Article Infectious disease Pulmonology Article has an altmetric score of 5

Stressed erythrophagocytosis induces immunosuppression during sepsis through heme-mediated STAT1 dysregulation

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Abstract

Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent RBCs (sRBCs). Macrophages are also essential in defense against microbial threats, but pathological states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype after intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, in that K. pneumoniae mutants lacking siderophore function recapitulated the findings observed with the WT strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and IFN-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulated the STAT1 pathway, with implications in severe infection.

Authors

Tolani F. Olonisakin, Tomeka Suber, Shekina Gonzalez-Ferrer, Zeyu Xiong, Hernán F. Peñaloza, Rick van der Geest, Yuting Xiong, David O. Osei-Hwedieh, Jesús Tejero, Matthew R. Rosengart, Wendy M. Mars, Daria Van Tyne, Andreas Perlegas, Samuel Brashears, Daniel B. Kim-Shapiro, Mark T. Gladwin, Michael A. Bachman, Eldad A. Hod, Claudette St. Croix, Yulia Y. Tyurina, Valerian E. Kagan, Rama K. Mallampalli, Anuradha Ray, Prabir Ray, Janet S. Lee

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Figure 4

K. pneumoniae enhances erythrophagocytosis, leading to upregulation of heme iron transcriptional responses and suppression of STAT1.

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K. pneumoniae enhances erythrophagocytosis, leading to upregulation of ...
(A) sRBC internalization in RAW cells incubated with vehicle (PBS), sRBCs (50 sRBC:1 Mφ), KP (MOI 10:1), or KP + sRBC for 90 minutes. (B) Quantification of sRBC uptake shown in A. (C) Bone marrow–derived macrophages (BMDMs) obtained from WT and Tlr4–/– mice were challenged with KP + sRBC (10sRBC:1 Mφ) for 2 hours. (B and C) n = 3 technical replicates per group and data are indicative of 2 independent experiments. *P < 0.05, **P < 0.01 by 2-tailed t test. (D) Intracellular CFU/mL in RAW cells that were challenged with KP or KP + sRBC for 90 minutes. (E and F) Heme iron transcriptional genes Hmox1, Scl40a1, and (G–K) Stat1 and STAT1 target genes C3, Cfb, Irf1, and Nos2 evaluated in RAW cells challenged with KP or KP + sRBC for 4 hours. (L–N) STAT1 and IRF1 immunoblots in RAW cells challenged with vehicle (PBS), sRBCs, KP, or KP + sRBC for 4 hours. Blots are indicative of at least 3 independent experiments. (O–Q) CCL5, CXCL10, and TNF-α were measured in cell culture supernatant by ELISA 4 hours after infection. (R–W) Stat1, C3, Cfb, Irf1, Nos2, and Rela in Stat1+/+ and Stat1–/– BMDMs challenged with KP or KP + sRBC for 4 hours. (E–K and R–W) Gene expression was evaluated by qPCR analysis. Fold change is relative to PBS-treated macrophages. Floating bar plots indicate median and 25% to 75% quartiles, n = 3 technical replicates per group. *P < 0.05, ***P < 0.001, ****P < 0.0001 by 2-tailed t test. (X and Y) CXCL10 and TNF-α were measured in cell culture supernatant by ELISA 4 hours after infection. (O–Q, X, and Y) n = 3 technical replicates per group. ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple comparisons test.

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